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Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.

Finnerty JR, Mazza ME, Jezewski PA - BMC Evol. Biol. (2009)

Bottom Line: MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function.This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. jrf3@bu.edu

ABSTRACT

Background: Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs.

Results: Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.

Conclusion: Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

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Msx Phylogeny based upon the full Msx alignment. Relationships among 44 metazoan Msx proteins were estimated by neighbor-joining (see methods). The tree is rooted using the two cnidarian sequences. Numbers at nodes indicate the percentage of replicates in which a given partition between taxa was observed in 1000 replicates of the bootstrap [106]. Circles indicate the major taxonomic group represented by each sequence (Hemi = Hemichordata, Ceph = Cephalochordata, Chon = Chondrichthyes, Amphib = Amphibia, Marsup = Marsupialia, Artio = Artiodactyla). Species abbreviations are provided in the methods.
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Figure 3: Msx Phylogeny based upon the full Msx alignment. Relationships among 44 metazoan Msx proteins were estimated by neighbor-joining (see methods). The tree is rooted using the two cnidarian sequences. Numbers at nodes indicate the percentage of replicates in which a given partition between taxa was observed in 1000 replicates of the bootstrap [106]. Circles indicate the major taxonomic group represented by each sequence (Hemi = Hemichordata, Ceph = Cephalochordata, Chon = Chondrichthyes, Amphib = Amphibia, Marsup = Marsupialia, Artio = Artiodactyla). Species abbreviations are provided in the methods.

Mentions: A neighbor-joining analysis of 44 Msx proteins is presented in Fig. 3. The tree depicted is based upon the full alignment and is rooted using the two cnidarian Msx sequences. All of the vertebrate Msx sequences appear as a monophyletic group, and within this vertebrate Msx clade, we can recognize distinct Msx1, Msx2, and Msx3 lineages. From the distribution of placental, marsupial, avian, amphibian, teleost, and chondrichthyan sequences among these three clades, we can conclude that the Msx1, 2, and 3 lineages had diverged prior to the evolutionary split between bony fishes and cartilaginous fishes. Furthermore, it appears that the Msx1 and Msx2 lineages share a common ancestor to the exclusion of Msx3. If we map the presence of conserved Msx domains on this phylogeny, it appears that MH1C has been lost independently in both the Msx2 and Msx3 families of vertebrates.


Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.

Finnerty JR, Mazza ME, Jezewski PA - BMC Evol. Biol. (2009)

Msx Phylogeny based upon the full Msx alignment. Relationships among 44 metazoan Msx proteins were estimated by neighbor-joining (see methods). The tree is rooted using the two cnidarian sequences. Numbers at nodes indicate the percentage of replicates in which a given partition between taxa was observed in 1000 replicates of the bootstrap [106]. Circles indicate the major taxonomic group represented by each sequence (Hemi = Hemichordata, Ceph = Cephalochordata, Chon = Chondrichthyes, Amphib = Amphibia, Marsup = Marsupialia, Artio = Artiodactyla). Species abbreviations are provided in the methods.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2655272&req=5

Figure 3: Msx Phylogeny based upon the full Msx alignment. Relationships among 44 metazoan Msx proteins were estimated by neighbor-joining (see methods). The tree is rooted using the two cnidarian sequences. Numbers at nodes indicate the percentage of replicates in which a given partition between taxa was observed in 1000 replicates of the bootstrap [106]. Circles indicate the major taxonomic group represented by each sequence (Hemi = Hemichordata, Ceph = Cephalochordata, Chon = Chondrichthyes, Amphib = Amphibia, Marsup = Marsupialia, Artio = Artiodactyla). Species abbreviations are provided in the methods.
Mentions: A neighbor-joining analysis of 44 Msx proteins is presented in Fig. 3. The tree depicted is based upon the full alignment and is rooted using the two cnidarian Msx sequences. All of the vertebrate Msx sequences appear as a monophyletic group, and within this vertebrate Msx clade, we can recognize distinct Msx1, Msx2, and Msx3 lineages. From the distribution of placental, marsupial, avian, amphibian, teleost, and chondrichthyan sequences among these three clades, we can conclude that the Msx1, 2, and 3 lineages had diverged prior to the evolutionary split between bony fishes and cartilaginous fishes. Furthermore, it appears that the Msx1 and Msx2 lineages share a common ancestor to the exclusion of Msx3. If we map the presence of conserved Msx domains on this phylogeny, it appears that MH1C has been lost independently in both the Msx2 and Msx3 families of vertebrates.

Bottom Line: MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function.This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. jrf3@bu.edu

ABSTRACT

Background: Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs.

Results: Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.

Conclusion: Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

Show MeSH
Related in: MedlinePlus